rs376907511

Positions:

• chr7-142752517-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BS2_Supporting

The NM_002769.5(PRSS1):​c.541A>G​(p.Ser181Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,461,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S181N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 41)
  • Exomes 𝑓: 0.000041 (1 hom.)
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.953

Genes affected

PRSS1 (HGNC:9475): (serine protease 1) This gene encodes a trypsinogen, which is a member of the trypsin family of serine proteases. This enzyme is secreted by the pancreas and cleaved to its active form in the small intestine. It is active on peptide linkages involving the carboxyl group of lysine or arginine. Mutations in this gene are associated with hereditary pancreatitis. This gene and several other trypsinogen genes are localized to the T cell receptor beta locus on chromosome 7. [provided by RefSeq, Jul 2008]

PRSS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a chain Serine protease 1 (size 223) in uniprot entity TRY1_HUMAN there are 19 pathogenic changes around while only 8 benign (70%) in NM_002769.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.13569438).
• BS2: High AC in GnomAdExome4 at 60 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.541A>G	p.Ser181Gly	missense_variant	4/5	ENST00000311737.12	NP_002760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12	c.541A>G	p.Ser181Gly	missense_variant	4/5	1	NM_002769.5	ENSP00000308720.7
PRSS1	ENST00000486171.5	c.583A>G	p.Ser195Gly	missense_variant	5/6	5		ENSP00000417854.1
PRSS1	ENST00000492062.1	c.391A>G	p.Ser131Gly	missense_variant	3/4	2		ENSP00000419912.2
PRSS1	ENST00000463701.1	n.1005A>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 41

GnomAD3 exomes AF: 0.0000636 AC: 16 AN: 251490 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135916

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000410 AC: 60 AN: 1461874 Hom.: 1 Cov.: 63 AF XY: 0.0000523 AC XY: 38 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Cov.: 41

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 21, 2024	The p.S181G variant (also known as c.541A>G), located in coding exon 4 of the PRSS1 gene, results from an A to G substitution at nucleotide position 541. The serine at codon 181 is replaced by glycine, an amino acid with similar properties. This variant was detected in a child with recurrent acute pancreatitis in conjunction with CFTR p.F508del; the child's healthy mother was also heterozygous for both variants (Corleto VD et al. BMC Gastroenterol, 2010 Oct;10:119). In HEK293 cells, this variant demonstrated similar autoactivation and secretion compared to wild type (Schnúr A et al. Gut, 2014 Feb;63:337-43). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 181 of the PRSS1 protein (p.Ser181Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with pancreatitis (PMID: 20950468). ClinVar contains an entry for this variant (Variation ID: 571921). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRSS1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PRSS1 function (PMID: 23455445). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 20, 2022

Variant summary: PRSS1 c.541A>G (p.Ser181Gly) results in a non-conservative amino acid change located in the trypsin domain (IPR001254) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251490 control chromosomes in the gnomAD database, however due to the presence of a highly homologous pseudogene for PRSS1, this finding should be interpreted with caution and allows no conclusion about variant significance. c.541A>G has been reported in the literature in the heterozygous state in a individual affected with acute recurrent pancreatitis, however this individual also had a common pathogenic variant in the heterozygous state in the CFTR gene and had no family history of pancreatitis, including his unaffected mother, who also harbored both variants (e.g. Corleto_2010). Therefore, this report does not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant with respect to protein autoactivation, secretion, and enzymatic activity (e.g. Schnur_2014). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	6.9
DANN	Benign	0.83
DEOGEN2	Uncertain	0.56	.;.;D;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.020	N
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.19	.;.;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N;.;N;N
REVEL	Benign	0.21
Sift	Benign	0.11	T;.;T;T
Sift4G	Benign	0.064	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.23
MVP		0.54
MPC		0.15
ClinPred		0.11	T
GERP RS		-5.0
Varity_R		0.26
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs376907511; hg19: chr7-142460368;